This invention relates to nucleic acids encoding for rat agouti related protein. Agouti related protein is a neuropeptide that may play a role in the central regulation of feeding behavior and energy metabolism via interactions with the melanocortin pathways.
While normally related to the production of black or yellow pigment in the hair, ubiquitous expression of agouti protein has been implicated in the occurrence of obesity and diabetes in yellow obese mice. Agouti related protein (AGRP; also known as ART and AGRT), a recently identified neuropeptide, shares some sequence homology with agouti protein and may play a role in the central regulation of feeding behavior and energy metabolism via interactions with the melanocortin pathways in a manner similar to agouti protein. When tested to see whether this homolog caused the onset of the same symptoms, it was observed that the overexpression of AGRT correlated with weight gain; see Graham et al., 1997 Nature Genetics 17:273-274 and Ollmann et al., 1997 Science 278:135-138. Moreover, AGRP mRNA is up-regulated in leptin-function deficient animals such as ob /ob and db /db mice (Shutter et al., Genes Dev. 11, 593,602, 1997).
The DNA sequence of AGRP has been reported for human and mouse; Shutter et al., 1997 Genes Dev. 11:593-602, Ollmann et al., 1997 Science 278:135-138. The human gene for ART is a 132-amino acid protein that is 25% identical to human agouti protein and is expressed primarily in the adrenal gland, subthalamic nucleus, and hypothalamus with a lower level of expression occurring in testis, lung, and kidney. The murine homolog of ART encodes a 131-amino acid protein that shares 81% amino acid identity to human ART with localized expression in the arcuate nucleus of the hypothalamus, the median eminence, and the adrenal medulla.
Attempts at detecting in situ hybridization signals of AGRP mRNA in rat brain with probes based on mouse AGRP sequences have proved unsuccessful. Since the rat is the primary animal model in the field of feeding regulation research, it is critical to characterize the function of AGRP in rats with the AGRP sequence from the same species. It is, thus, an object of the present invention to provide a compound that can recapitulate these same symptoms in rats so as to further our current knowledge in the field of feeding regulation. Such a compound could be used for developing tools to characterize the biological function of this neuropeptide, and to discover new drugs which modulate AGRP and melanocortin functions.
This invention relates to isolated nucleic acids encoding rat agouti related protein. Preferred embodiments include nucleic acid of the sequence set forth in SEQ ID NO:1 and nucleic acids which are complementary to it. This invention also relates to the protein encoded thereby (rat AGRP), vectors comprising said nucleic acid, and host cells comprising said vectors. Lastly, the present invention relates to processes utilizing the nucleic acids or protein of the present invention, such as the generation of antibodies to rat AGRP through the injection of fragments or full length rat AGRP into rabbits and recovery of the antibodies therefrom.